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Hydrochloric Acid → Methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate

HRID 1509676
Notes
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Reaction equation

HRID 1509676 reaction equation
[CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9]C(C)(C)C)=O)[C@H:4]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([B:35]2[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]2)=[CH:29][CH:28]=3)[CH2:3]1.Cl.[CH3:45][O:46][C:47]([NH:49][C@@H:50]([CH:54]([CH3:56])[CH3:55])C(O)=O)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:55][CH:54]([CH3:56])[C@H:50]([NH:49][C:47](=[O:48])[O:46][CH3:45])[C:7]([N:5]1[CH2:6][C@@H:2]([CH3:1])[CH2:3][C@H:4]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]1[C:27]2[C:32]([CH2:33][O:34][C:21]=1[CH:20]=3)=[CH:31][C:30]([B:35]1[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:42])([CH3:43])[O:36]1)=[CH:29][CH:28]=2)=[O:9]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 178461438HCID 178461438, compound

Product 1

HCID 178502425
Methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate
Yield 57.3%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(2S,4S)-tert-butyl 4-methyl-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (950 mg, 1.63 mmol) was dissolved in DCM (12 mL), MeOH (3 mL) and HCl (4 M in dioxane, 3 mL) was added. The reaction mixture was stirred for 4 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (285 mg, 1.63 mmol), HATU (620 mg, 1.63 mmol) and DMF (15 mL), then DIPEA (1.42 mL, 8.15 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate (596 mg, 57%).

Workup

  1. concentrationconcentrated under reduced pressure
  2. waitAfter 1 h
  3. washwashed successively with saturated aqueous NaHCO3 and brine
  4. dry with materialThe organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc)

Sources & evidence

ORD record
ord-c516f8e067024aa5aaaeea70569fe5a2
Source dataset
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09221833B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes